With the rapid rise in the incidence and prevalence of obesity and type 2 diabetes, diabetic complications pose a heavy healthcare burden in the U.S.A. and throughout the world. This proposal is based on the innovative idea that insulin/PI3K signaling regulates ion currents in the heart, and channelopathies caused by reduced PI3K signaling contribute to the development of diabetic arrhythmogenic complications. The proposal investigates how PI3K signaling regulates the function of (1) a nonselective cation channel (HCN) that modulates the firing of pacemakers in the cardiac conduction system and (2) a sodium channel (Nav1.5) that regulates the cardiac action potential. The biophysical and biochemical studies in Aims 1 & 2 combine molecular mutagenesis, electrophysiology and phospho-proteomics to investigate how HCN and Nav1.5 are regulated by PI3K signaling. The animal studies in Aims 1 & 2 investigate how reduced PI3K signaling perturbs the function of HCN and Nav1.5 and alters physiology in native cardiac tissues. The high-fat diet experiments to induce insulin resistance will determine whether changes in the activity of Nav1.5 produce cardiac electrophysiological abnormalities in vivo. The clinical study in Aim 3 takes advantage of heart tissue routinely excised during cardiac surgery to test the hypothesis that decreased insulin/PI3K signaling due to insulin resistance is associated with (1) increased persistent sodium current (mediated by Nav1.5) and QT interval prolongation, and (2) reduced pacemaker current (mediated by HCN) in humans. In summary, studies in this proposal will yield important translational results that give us a mechanistic understanding of channelopathies caused by reduced insulin/PI3K signaling accompanied by significant clinical implications for the management of diabetic complications.